Hypoinsulinemic Hypoglycemia Triggered by Liver Injury in Elderly Subjects with Low Body Weight: Case Reports

ID: 17-0155 10.1530/EDM-17-0155

T Anno and others Hypoglycemia triggered by liver ID: 17-0155; February 2018 injury DOI: 10.1530/EDM-17-0155

Hypoinsulinemic hypoglycemia triggered by liver injury in elderly subjects with low body weight: case reports

Takatoshi Anno1, Hideaki Kaneto2, Ryo Shigemoto1, Fumiko Kawasaki1, Yasuhiro Kawai1, Noriyo Urata3, Hirofumi Kawamoto3, Kohei Kaku1 and Niro Okimoto1 Correspondence should be addressed 1Department of General Internal Medicine 1, Kawasaki Medical School, Okayama, Japan, 2Department of Diabetes, to T Anno Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan, and 3Department of General Internal Email Medicine 2, Kawasaki Medical School, Okayama, Japan [email protected]

Summary

Hypoglycemia is induced by many causes, especially over-dose of insulin or oral hypoglycemic agents in diabetic subjects. In such a case, hyperinsulinemic hypoglycemia is usually observed. On the other hand, it is important to classify secondary hypoglycemia and hypoinsulinemic hypoglycemia. Liver injury-induced hypoglycemia is one of the causes of hypoinsulinemic hypoglycemia but rarely observed in clinical practice. Herein, we experienced similar 2 cases of non- diabetic hypoinsulinemic hypoglycemia. Both of them were elderly subjects with low body weight. Furthermore, it is likely that hypoinsulinemic hypoglycemia in both subjects was triggered by severe liver injury, at least in part, due to possible limited liver glycogen store. In elderly subjects with low body weight and/or malnutrition, metabolism in the liver is reduced and glycogen accumulation is decreased. Such alteration brings out acute and marked liver injury, which finally leads to the onset of severe hypoglycemia. It is known that not only liver injury but also multiple organ failure could be induced due to extreme emaciation in subjects. It is likely that in elderly subjects with low body weight and/or malnutrition, multiple organ failure including liver failure could be induced due to the similar reason. Therefore, we should be very careful of such subjects in order to avoid the development of multiple organ failure which leads to life-threatening situations. In conclusion, we should keep in mind the possibility of hypoinsulinemic hypoglycemia when we examine severe liver injury, especially in elderly or starving subjects with low body weight and limited liver glycogen stores.

Learning points:

•• It is important to classify secondary hypoglycemia and hypoinsulinemic hypoglycemia. •• Liver injury-induced hypoglycemia is one of the causes of hypoinsulinemic hypoglycemia but rarely observed in everyday clinical practice. •• Herein, we reported similar 2 cases of hypoinsulinemic hypoglycemia without diabetes presumably triggered by severe liver injury. •• In both cases, hypoglycemia was improved by glucose infusion, although their liver injury was not improved. •• We should keep in mind the possibility of hypoinsulinemic hypoglycemia when we examine severe liver injury, especially in elderly subjects with low body weight.

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Background had very severe liver injury as follows: (case 1) T-Bil: 1.7 mg/dL U/L; AST: 1102 U/L; ALT: 401 U/L; ALP: 2113 U/L; Hypoglycemia is induced by many causes, especially over- γ-GTP: 88 U/L; LDH: 704 U/L; (case 2) T-Bil: 2.2 mg/ dose of insulin or oral hypoglycemic agents in diabetic dL U/L; AST: 2363 U/L; ALT: 1797 U/L; ALP: 4068 U/L; subjects. In such a case, hyperinsulinemic hypoglycemia γ-GTP: 101 U/L; LDH: 1040 U/L (Fig. 1). In both cases, HBs is usually observed. On the other hand, it is difficult antigen, HCV antibody and antinuclear antibody were to diagnose hypoinsulinemic hypoglycemia, which is negative. Inflammation markers were as follows: (case 1) sometimes observed in adult non-diabetic subjects (1, 2). WBC: 15 250/μL; Neut: 92.0%; CRP: 0.64 mg/dL; (case 2) Liver injury is one of the causes of hypoglycemia. WBC: 20 820/μL; Neut: 90.3%; CRP: 2.21 mg/dL. Anemia The major case of acute liver failure is hepatitis virus was observed in both cases: (case 1) RBC: 277 × 104/μL, Hb: infection or drug-induced liver damage, but in many 8.5 g/dL; (case 2) RBC: 333 × 104/μL, Hb: 10.5 g/dL, but fecal cases, the cause of liver failure remains unknown (3). Hb was negative and renal function was normal. Chest Liver injury-induced hypoglycemia is thought to show and abdominal computed tomography and abdominal hypoinsulinemic hypoglycemia but rarely observed in ultrasonography revealed inflectional area of chest, a clinical practice. However, recently, we experienced 2 little of pleural effusion and ascites in both cases (Fig. 2). similar cases of elderly subjects with hypoinsulinemic In such image inspection, there was no lesion indicating hypoglycemia both of which were presumably triggered malignancy. Both cases did not have hypoglycemia or by severe liver injury. These cases are very rare, and there liver dysfunction 1–2 months before. Laboratory data were many similarities between these 2 cases. 2 months before in case 1 were as follows: PG: 129 mg/ dL; HbA1c: 4.9%; AST: 14 U/L; ALT: 7 U/L; γ-GTP: 20 U/L; LDH: 238 U/L. Laboratory data 1 month before in case 2 Case presentation were as follows: PG: 98 mg/dL; AST: 18 U/L; ALT: 24 U/L; Case 1 was an 83-year-old woman who had old cerebral γ-GTP: 12 U/L; LDH: 191 U/L. infarction and Alzheimer dementia treated with Table 2 shows time course of various clinical data rivastigmine and was admitted to our hospital due to in both cases. Because of various findings including low coma, hypothermia and hypoglycemia. Three days before NH3 levels (48 μg/dL in case 1 and 37 μg/dL in case 2), she started having therapy with sulbactam/ampicillin prothrombin activity (43.8% and 60.9%), PT-INR (1.50 and for pneumonia. Case 2 was a 79-year-old man who 1.27), we could not diagnose these patients as acute liver had hypertension treated with irbesartan/amlodipine failure or fulminant hepatic failure with confidence. In and dementia with Lewy bodies treated with donepezil both cases, the cause of liver injury remained unknown. In hydrochloride and was admitted to our hospital due to both cases, hypoglycemia was improved with intravenous coma, hypothermia and hypoglycemia. From 1 month glucose injection and subsequent continuous glucose before, he had suffered from repeated aspiration infusion, but their liver injury was not improved in both pneumonia. cases. Fifteen days and thirteen days after the admission, Body weight and BMI in both cases were very low. case 1 and case 2 died of multiple organ failure including Height, body weight, BMI in case 1 and case 2 were liver injury (Fig. 1). 140.0 cm, 31.9 kg, 16.3 kg/m2 and 159.0 cm, 39.0 kg, 15.4 kg/m2, respectively. On admission, body temperature, Discussion blood pressure, heart rate, saturation of arterial blood oxygen in case 1 and case 2 were 34.9°C, 107/58 mmHg, As a cause of hypoglycemia, there are mainly 2 types: 41 beats/min, 97.0% and 34.0°C, 92/76 mmHg, 89 beats/ hyperinsulinemic hypoglycemia and hypoinsulinemic min, 93.0%, respectively. Table 1 shows clinical hypoglycemia. Hyperinsulinemic hypoglycemia is usually characteristics and results of biochemical studies in 2 observed after over-dose of insulin or oral hypoglycemic cases. Both cases showed hypoinsulinemic hypoglycemia. agents in diabetic subjects. In such a case, hypoglycemia is Plasma glucose (PG) level in case 1 was as low as 10 mg/ caused by hyperinsulinemia or exaggerated insulin action. dL. Serum insulin and C-peptide levels in case 1 were as On the other hand, hypoinsulinemic hypoglycemia low as <1.0 μU/mL and 0.1 ng/mL, respectively. Similarly, is mainly caused by reduction of glycogenolysis and/ PG level in case 2 was as low as 37 mg/dL. Serum insulin or gluconeogenesis and consequent decrease of and C-peptide levels in case 2 were also as low as <1.0 μU/ blood glucose levels. Furthermore, in both cases with mL and 0.3 ng/mL, respectively. In addition, both cases hyperinsulinemic or hypoinsulinemic hypoglycemia http://www.edmcasereports.com 2 Downloaded from Bioscientifica.com at 09/24/2021 03:53:29PM via free access T Anno and others Hypoglycemia triggered by liver ID: 17-0155; February 2018 injury DOI: 10.1530/EDM-17-0155

Table 1 Clinical characteristics of 2 cases with hypoinsulinemic hypoglycemia triggered by severe liver injury.

Normal range Case 1 Case 2 Age (years old) 83 79 Gender female male Height (cm) 140.0 159.0 Body weight (kg) 31.9 39.0 Body mass index (kg/m2) 16.27 15.43 Red blood cell count (x104 /μL) 435–555 277 333 Hemoglobin (g/dL) 13.7–16.8 8.5 10.5 White blood cell count (/μL) 3300–8600 15250 20820 Neutrophil (%) 52.0–80.0 92.0 90.3 Lymphocyte (%) 20.0–40.0 6.0 7.9 Platelet (x104 /μL) 15.8–34.8 22.4 6.7 C-reactive protein (mg/dL) <0.14 0.64 2.21 Plasma glucose level (mg/dL) 10 37 IRI (μU/mL) 0.0–10.0 <1.0 <1.0 C-peptide levels (ng/mL) 0.8–2.5 0.1 0.3 HbA1c (4.9 – 6.0 %) 4.9 5.7 Adrenocorticotropic hormone (pg/mL) 7.2–63.2 26.9 2.2 Cortisol (μg/dL) 4.5–21.1 72.6 69.3 Growth hormone (μIU/mL) 29.58 6.93 Insulin-like growth factor 1 (ng/mL) ≤10 ≤10 Total Bilirubin (mg/dL) 0.4–1.5 1.7 2.2 Aspartate aminotransferase (U/L) 13–30 1102 2363 Alanine aminotransferase (U/L) 10–42 401 1797 Alkaline phosphatase (U/L) 106–322 2113 4068 Gamma-glutamyltransferase (U/L) 13–64 88 101 Lactate dehydrogenase (U/L) 124–222 704 1040 Ammonia (μg/dL) 12–66 48 37 Hepatitis A virus antibody, immunoglobulin M 0.16 (–) N/A Quantitation of hepatitis B virus DNA (LC/mL) n.d. n.d. Hepatitis C virus antibody 0.2 (–) 0.1 (–)

N/A, not applicable; n.d., not detected. when glucose levels are decreased, several stress responses pneumonia, there is a possibility that pneumonia and/ occur to maintain the normoglycemic state. For example, or drug were involved in the onset of hypoglycemia and insulin secretion is reduced and various counter liver injury. We think that hypoglycemia was associated regulatory hormones such as glucagon are increased, with severe liver injury in both cases. They did not have which leads to glycogenolysis and gluconeogenesis. renal failure and did not taken oral drugs which could Hypoglycemia occurs when gluconeogenesis fails, induce hypoinsulinemic hypoglycemia. Moreover, their especially in cases of severe malnutrition such as anorexia laboratory analyses revealed that both patients did not nervosa patients with decreased liver glycogen stores (4). suffer from hypopituitarism, adrenal insufficiency and Similarly, malnutrition with elderly or starving subjects hypothyroidism. Both subjects had medical history of also seemed to be status of gluconeogenesis failure dementia and were in low nutritional status. They were and low glycogen stores. It is known that insufficiency elderly subjects with low body weight and, although or deficiency of various counter regulatory hormones speculative, with possible limited liver glycogen stores. against hypoglycemia further facilitates hypoinsulinemic In such a case, we have to consider Kwashiorkor-type hypoglycemia. Therefore, it is important to classify malnutrition (6, 7). It is known that Kwashiorkor- secondary hypoglycemia (5) and hypoinsulinemic type malnutrition also causes fatty liver and/or liver hypoglycemia (1, 2). Herein, we reported 2 similar cases dysfunction same as anorexia nervosa. Although our cases of non-diabetic hypoinsulinemic hypoglycemia patients did not have fatty liver in the abdominal ultrasonography with severe liver injury. In both cases, patients were and computed tomography, it is possible that our elderly subjects with dementia and low body weight. cases suffered from Kwashiorkor-type malnutrition. However, they did not have hypoglycemia or liver injury Taken together, we assume that their hypoinsulinemic one or two month before. Since both cases suffered from hypoglycemia was induced by severe liver injury in both

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Table 2 Time course of liver injury and undernutrition.

Day 1 Day 6 Day 10* Case 1 T-BIL (mg/dL) 1.7 2.0 3.3 AST (U/L) 1102 1192 993 ALT (U/L) 401 576 643 ALP (U/L) 2113 3661 4132 γ-GTP (U/L) 88 162 247 LDH (U/L) 704 893 867

NH3 (μg/dL) 48 PA (%) 43.8 66.0 61.7 PT-INR 1.50 1.22 1.26 WBC count (/μL) 15250 8200 4030 Lymphocyte (%) 6.0 8.0 9.0 Platelet (x104 /μL) 22.4 9.7 6.1 Albumin (g/dL) 3.7 3.1 3.1 Cholinesterase (IU/L) 178 156 165 Case 2 T-BIL (mg/dL) 2.2 1.4 1.4 Figure 1 AST (U/L) 2363 865 594 Clinical time course in case 1 and case 2: hypoglycemia and liver injury were observed on admission. Their hypoglycemia was improved with ALT (U/L) 1797 917 572 intravenous glucose injection and subsequent continuous glucose ALP (U/L) 4068 2695 2390 infusion, but their liver injury was not improved in both cases. γ-GTP (U/L) 101 94 132 LDH (U/L) 1040 624 656 NH (μg/dL) 37 elderly subjects with low body weight. Unfortunately, 3 PA (%) 60.9 60.9 67.8 liver biopsies were not done in both cases. However, we PT-INR 1.27 1.27 1.21 think malnutrition were, at least in part, associated with WBC count (/μL) 20820 7560 2420 liver failure. Lymphocyte (%) 7.9 11.0 17.0 Platelet (x104 /μL) 67 20 46 Another problem was causes of severe liver injury. Albumin (g/dL) 2.2 1.7 1.8 On admission, there was not enough information with Cholinesterase (IU/L) 108 91 95 which we could diagnose them as acute liver failure or *Data presented is Day 11 for Case 2. T-BIL, totla bilirubin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; γ-GTP, gamma glutamyltransferase; LDH, lactate dehydrogenase; NH3, ammonia; PA, prothrombin activity; INR-PT, international normalized ratio of prothrombin time; WBC, white blood cells.

fulminant hepatic failure, because of their normal range of NH3 levels, PT-INR ≤1.5 and PT activity >40%, even within 8 weeks of the first symptoms. It is known that major case of acute liver failure is hepatitis virus infection or drug-induced liver damage. In our cases, however, hepatitis virus was not detected, and there was no possible drug that induces liver damage before admission to our hospital. While in many cases the cause of liver failure remains unknown, the cause of severe liver injury in our cases also remained unknown. Unfortunately, in both cases, they died of multiple organ failure including severe liver injury in spite of the improvement of hypoglycemia by continuous glucose infusion.

Figure 2 The most important message, which we would like to Chest computed tomography (CT), abdominal CT and abdominal convey through this manuscript is as follows: in elderly ultrasonography (US) in case 1 and case 2: in both cases, chest and subjects with low body weight and/or malnutrition, abdominal computed tomography revealed inflectional area of chest, a little of pleural effusion and ascites. metabolism in the liver is reduced and glycogen http://www.edmcasereports.com 4 Downloaded from Bioscientifica.com at 09/24/2021 03:53:29PM via free access T Anno and others Hypoglycemia triggered by liver ID: 17-0155; February 2018 injury DOI: 10.1530/EDM-17-0155 accumulation is decreased. Such alteration brings out patient’s next-of-kin (her daughter). A copy of the consent is available acute and marked liver injury which finally leads to for review by the Editor-in-Chief of this journal. Second case (the patient died): Informed consent for publication of this case report and any the onset of severe hypoglycemia. Therefore, in case of accompanying images was obtained from the patient’s next-of-kin (his hypoinsulinemic hypoglycemia, we should keep in mind wife). A copy of the consent is available for review by the Editor-in-Chief the possibility that such hypoinsulinemic hypoglycemia of this journal. is induced by severe liver injury. It is known that not only liver injury but also multiple organ failure could be induced due to extreme emaciation in subjects (e.g. Author contribution statement subjects with anorexia nervosa). It is likely that in elderly T A and H K researched data and wrote the manuscript. R S, F K, Y K and N U researched data and contributed to the discussion. H K, K K and N O subjects with low body weight and/or malnutrition, reviewed the manuscript. multiple organ failure including liver failure could be induced due to the similar reason. Therefore, we should be very careful of such subjects in order to avoid the development of multiple organ failure which leads to life- References threatening situations. 1 Griffiths MJ & Gama R. Adult spontaneous hypoglycaemia. In conclusion, we should keep in mind the possibility Hospital Medicine 2005 66 277–283. (https://doi.org/10.12968/ hmed.2005.66.5.18421) of hypoinsulinemic hypoglycemia when we examine 2 Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, severe liver injury, especially in elderly or starving subjects Seaquist ER, Service FJ & Endocrine Society. Evaluation and with low body weight and limited liver glycogen stores. management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism 2009 94 709–728. (https://doi.org/10.1210/ jc.2008-1410) Declaration of interest 3 Bernal W & Wendon J. Acute liver failure. New England Journal The authors declare that there is no conflict of interest that could be of Medicine 2013 369 2525–2534. (https://doi.org/10.1056/ perceived as prejudicing the impartiality of the research reported. NEJMra1208937) 4 Norris ML, Harrison ME, Isserlin L, Robinson A, Feder S & Sampson M. Gastrointestinal complications associated with anorexia nervosa: a systematic review. International Journal of Eating Disorders 2016 49 216–237. (https://doi.org/10.1002/eat.22462) Funding 5 Service FJ. Hypoglycemic disorders. New England Journal of This research did not receive any specific grant from any funding agency in Medicine 1995 332 1144–1152. (https://doi.org/10.1056/ the public, commercial or not-for-profit sector. NEJM199504273321707) 6 Leitner ZA. Postoperative malabsorption: secondary protein malnutrition syndrome. Lancet 1958 2 504–507. (https://doi. org/10.1016/S0140-6736(58)91288-1) Patient consent 7 Krikler DM & Schrire V. Kwashiorkor in an adult due to an intestinal First case (the patient died): Informed consent for publication of this blind loop. Lancet 1958 8 510–511. (https://doi.org/10.1016/S0140- case report and any accompanying images was obtained from the 6736(58)90815-8)

Received in final form28 January 2018 Accepted 6 February 2018

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